摘要/Abstract

以樟脑为原料合成了22个樟脑基缩氨基硫脲衍生物，通过¹H NMR、¹³C NMR和HRMS对其结构进行了表征，并通过单晶X射线衍射测定了2-（3-（4-吡啶基）-1，7，7-三甲基二环[2.2.1]庚-2-亚基）肼硫代甲酰胺（3n）的晶体结构.通过3-（4，5-二甲基吡啶-2-基）-5-（3-羧基甲氧基苯基）-2-（4-磺苯基）-2H-四唑（MTS）法探索了这些衍生物对人乳腺癌细胞（MDA-MB-231）、人肺腺癌细胞（A549）和人多发性骨髓瘤细胞（RPMI-8226）三株肿瘤细胞的抗增殖活性以及对正常人细胞（GES-1）的细胞毒性.结果表明，这些衍生物都表现出较好的抗肿瘤活性，且对正常细胞GES-1毒性低（IC₅₀>50 μmol·L^-1）.其中，2-（3-（4-蒽亚苄基）-1，7，7-三甲基二环[2.2.1]庚-2-亚基）肼硫代甲酰胺（3s）对MDA-MB-231细胞表现出最强的抗肿瘤活性[IC₅₀＝（3.90±0.04）μmol·L^-1].此外，初步的抗肿瘤机制结果表明，化合物3s可以通过细胞内活性氧（ROS）的增加和线粒体膜电位的破坏，诱导MDA-MB-231细胞的G2期阻滞和剂量依赖式凋亡，且通过凋亡相关蛋白的变化对实验结果进行了验证.
关键词: 樟脑基缩氨基硫脲, 抗肿瘤活性, G2期阻滞, 活性氧(ROS), 线粒体凋亡通路
22 novel camphor-based thiosemicarbazone derivatives were synthesized using camphor-based thiosemicarbazone as material and their structures were determined by ¹H NMR, ¹³C NMR and HRMS. The crystal structure of 2-(3-(pyridin-4-ylmethylene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)hydrazinecarbothioamide (3n) was determined by single crystal X-ray diffraction. The derivatives were screened in vitro for anticancer activities against human breast cancer cell line (MDA-MB-231), human lung adenocarcinoma cell line (A549), human multiple myeloma cell line (RPMI-8226) and toxicity against a normal human cell line (GES-1) by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). It was found that majority of the tested analogs showed moderate to significant antitumor activity against selected cancer cell lines. Noticeably, 2-(3-(anthracen-9-ylmethylene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)-hydrazinecarbothioamide (3s) exhibited selective anti-tumor activities against MDA-MB-231 cells (IC₅₀=3.90±0.04 μmol·L^-1) and low toxicity to GES-1 cells (IC₅₀>50 μmol·L^-1). In the process of exploring the underlying mechanism of 3s, it was found that compound 3s could cause G2 phase arrest and apoptosis in MDA-MB-231 cells by overproduction of intracellular reactive oxygen species and collapse of mitochondrial membrane potential. The measured results were confirmed by western blot assay.
Key words: camphor-based thiosemicarbazone, anti-tumor activity, G2 phase arrest, reactive oxygen species (ROS), mitochondrial apoptosis pathway


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